The use of transdermal patches for the delivery of various drug systems has met with increasing success in the pharmaceutical industry, particularly in view of specific problems which have arisen in connection with drugs taken by other means, and because of their implications in terms of long-term application of drugs in a particularly simple manner.
One of the specific problems which has been encountered in connection with the use of various drugs has been the ability to apply a drug in a simple or monolithic system which employs the drug in admixture with an adhesive base system for application to the skin. The ability to do this with various types of drugs can be impeded by various considerations, such as differences in viscosity, solubility, therapeutic drug delivery rate, and the like.
One type of system which has been developed includes a polyisobutylene-based adhesive system preferably including a plasticizer for the polyisobutylene and a drug which is moderately soluble in that plasticizer.
One such system, for example, is set forth in Chandrasekaran et al., U.S. Pat. No. 4,201,211, which describes a five-layer therapeutic transdermal delivery system. The device in Chandrasekaran et al. specifically discloses a skin patch for administering the drug clonidine continuously and transdermally in a controlled manner for long time periods, in this case for the purpose of effecting .alpha.-andrenergic stimulation. The transdermal patch in this case includes a backing layer, a clonidine reservoir layer, a control membrane, a skin contact adhesive, and a release liner.
The particular clonidine reservoir layer employed by Chandrasekaran et al. includes, in addition to the clonidine, an organic, apolar, non-volatile, inert liquid such as mineral oil, and a blend of polyisobutylenes. These generally include mixtures of a low molecular weight polyisobutylene of 35,000 to 50,000 viscosity average molecular weight and a high molecular weight polyisobutylene of from 1 million to 1.5 million viscosity average molecular weight. The clonidine thus is carried by the mineral oil because of its limited solubility. The broad disclosure of this patent indicates that from 35% to 65% by weight of the mixture in the clonidine reservoir comprises each of the mineral oil and polyisobutylene blend. In the example in this patent, a ratio of mineral oil to polyisobutylene of about 0.9 is utilized.
In order to control the release of the drug in this case, a rate-controlling membrane is laminated between sheets of adhesive. The adhesive compositions employed in this patent demonstrate low viscosity and poor cohesive strength, and leave an unacceptable amount of residue on the skin upon removal of the patch. Furthermore, the need to use a microporous membrane not only requires great care to ensure that no air pockets arise within the membrane, but it greatly increases the complication and cost of manufacturing same.
In accordance with Enscore et al., U.S. Pat. No. 4,559,222, another transdermal patch for the delivery of a variety of drugs including clonidine is disclosed. In this system, a six-layer skin patch is disclosed including a backing layer, a drug reservoir layer, a control membrane, a skin contact adhesive layer, a prime coat layer, and a release liner. The drug delivery matrix disclosed in Enscore et al. includes mineral oil, polyisobutylene, and a moderately mineral-oil-soluble drug, along with at least 6% colloidal silicon dioxide, which is employed to increase the viscosity of the matrix composition. The compositions disclosed in this patent include a ratio of mineral oil to polyisobutylene of at least 1.0 and are characterized by viscosities of at least 1.5 times 10.sup.7 poise. This patentee, in fact, discloses data which is said to indicate that at increasing MO/PIB ratios the clonidine release rate also increases. Thus, such ratios below about 1.0 are said to have undesirably low drug permeability, as is specifically shown in FIG. 5 thereof.
This patentee also discloses, however, that when adding colloidal silicon dioxide the adhesion of the skin contact adhesive to the release liner is considerably increased, and as is noted in column 4 of that patent, 5 to 10 micron thick prime coats of 53% PIB/47% mineral oil were then applied between the skin contact adhesive and the liner to counteract such effects. The addition of the prime coat results, however, in a more complicated and a more costly manufacturing process. In addition, since the adhesive layer which actually contacts the skin does not contain colloidal silicon dioxide, it has a lower cohesive strength leaving residue on the skin when the system is removed.
Ueda et al., U.S. Pat. No. 4,889,721, disclose a transdermal system which includes at least two adhesive layers in which one of the layers other than the one furthest from the skin contains a solid powder which can include, inter alia, zinc oxide. The rate of drug release is thus said to be variable based upon the quantity and type of solid powder used. Clonidine is mentioned among the large number of drugs in this patent, and is mentioned as being potentially incorporated in a layer with the solid powder. Various adhesives are mentioned other than the plasticizer combination with polyisobutylene.
Sablotsky et al., U.S. Pat. Nos. 4,994,267 and 4,814,168 disclose transdermal compositions which can include large numbers of different drug compositions including clonidine. In this case, however, specific adhesive systems are mentioned including an acrylate polymer and rubber (e.g., polyisobutylene), in which materials such as zinc oxide and magnesium oxide and the like are used as cross-linking agents for carboxylic acid groups.
Wang et al., European Patent No. 525,105, disclose polyisobutylene adhesive compositions in transdermal drug delivery devices which include an oily, non-polar liquid active agent dissolved in a mixture of high molecular weight polyisobutylene and low molecular weight polyisobutylene, and in which the composition is substantially free of plasticizers and tackifiers.
Horiuchi et al., U.S. Pat. No. 4,880,416, disclose a dermal bandage including a large variety of drugs, including clonidine, in which various metal oxides, including zinc oxide, can be added to neutralize polycarboxylic acids dissolved in a vinyl acetate polymer.
Suzuki et al., U.S. Pat. No. 5,413,794, disclose drug administering systems for drugs such as clonidine, and also mention adhesion promoters, plasticizers, antioxidants, and certain unspecified fillers compounded with rubber adhesives such as polyisobutylene. Zinc oxide is mentioned as an inorganic filler for poultices containing hydrophilic polymer bases.
Sablotsky et al., U.S. Pat. No. 5,300,291, disclose the use of pressure-sensitive adhesives of mixtures of rubber, such as polyisobutylene, and a multipolymer to which clays are added for increased adhesiveness. Zinc oxide is mentioned along with calcium carbonate, silicas, and the like.
Nagai et al., U.S. Pat. No. 5,164,416 discloses the use of limonene as a penetration enhancer. Once again, zinc oxide is mentioned as an inorganic filler for poultices containing hydrophilic polymer bases.
The search has therefore continued for improved drug delivery systems for the transdermal application of drugs of this type.